Filamentous tau inclusions in neurons, astrocytes and oligodendrocytes are the neuropathological hallmark of both sporadic and familial tauopathies. Alzheimer's disease (AD), the most common tauopathy, is characterized by the deposition of numerous Ap-rich senile plaques as well as neurofibrillary tangles composed of hyperphosphorylated tau in the brains of affected individuals. Compelling evidence in support of the hypothesis for a causative role of tau in neurodegeneration is provided by the studies of tauopathies other than AD, which demonstrate abundant filamentous pathology in the absence of extracellular amyloid deposition. Furthermore, the identification of pathogenic tau gene mutations in familial tauopathies, termed frontotemporal dementia with parkinsonism linked to chromosome 17, provided unequivocal support for the hypothesis that defects in the tau gene alone are sufficient to cause neurodegeneration. These tau gene mutations are pathogenic because they perturb alternative splicing, alter the biophysical properties and/or affect the microtubule binding function of tau. However, it remains unclear why in both sporadic and familial tauopathies there is selective degeneration of specific subsets of neurons and glia. To test the hypothesis that additional genetic or epigenetic perturbations that alter the expression, function or biochemical properties of the tau protein lead to distinct topographic and cell-type specific neurodegeneration, the following specific aims are proposed: 1) An analysis of cell-type specific differences in the expression and biochemical properties of tau in brain tissue form both sporadic and familial tauopathies. 2) Development of transgenic mice that overexpress human wild type or mutant tau utilizing promoters that drive expression in specific cell lineages. The development of tau pathology in the specific cell types will be assessed morphologically and biochemically. 3) Determine mechanisms of tau-mediated neurodegeneration in primary cultures of neurons, astrocytes and oligodendrocytes derived from the brains of the transgenic animals developed in Aim 2. These studies will provide invaluable information on the pathogenesis of filamentous tau inclusions in the specific cell lineages within the brain, thus providing insight into the phenotypic expression of tauopathies. The successful generation of animal models will accelerate future research to discover new techniques for the diagnosis and treatment of tauopathies, including AD, the most dementing illness characterized by prominent tau pathology. This proposal will also facilitate my transition from a trainee to a fully independent experimental neuropathologist.